Rheumatoid arthritis is a chronic inflammatory disease that primarily affects the joints. IgM and IgG autoantibodies reactive with the Fc fragment of IgG (rheumatoid factors, RF) are the hallmark of the disease. Understanding the structural and genetic basis for RF synthesis, and the reasons for sustained RF production in rheumatoid arthritis, is the long term objective of this research grant proposal. We have characterized antibodies that identify both variable region subgroups, and cross-reactive idiotypes (CRIs) on RFs, and have demonstrated that the light chains on monoclonal RFs from unrelated people are structurally related. Two V kappa genes (Humkv325 and Humkv328) that can encode human RF light chains were isolated and sequenced. The Humkv325 gene is utilized repeated in chronic lymphocytic leukemia, a lymphoproliferative disease that is often associated with autoantibody production. Other experiments revealed that IgM RF precursors are abundant in the blood and bone marrow of normal people, despite the absence of overt RF synthesis. Transient expansion of the IgM RF precursor cell pool regularly accompanies anamnestic immune responses. In rheumatoid arthritis, therefore, it is aberrant regulation of RF synthesis and diversification that is fundamental to the disease process, rather than the mere presence of the autoantibody. The proposed experiments intend to determine the causes of the abnormal regulation and to devise methods to overcome it. The specific aims of the experiments are: (1) to define the structural and genetic basis for three distinct CRIs on human monoclonal RF heavy chains; (2) to characterize the idiotypes and genes used for polyclonal RF synthesis in the blood and synovium of patients with rheumatoid arthritis; (3) to clarify the physiologic function of the RF CRI precursor B cells, by studying their distribution in lymphoid organs, their utilization in antibody responses against exogenous antigens, and their role in the processing of antigen-antibody complexes; (4) to discern how the HLA DR antigens Dw4 and DR1 may predispose to abnormally sustained RF production following exposure to an environmental antigen (Epstein-Barr virus gp110) that reproduces the rheumatoid arthritis susceptibility determinant in the DR beta-1 chain; and (5) to develop therapies that can prevent or terminate RF autoantibody production in experimental animals, and eventually in patients with rheumatoid arthritis and other RF-associated illnesses.